The genus Aloe (Liliaceae) is a shrubby tropical/subtropical plant which has succulent and elongate leaves. Of the more than 360 Aloe species known, Aloe barbadensis Miller (Aloe vera Linne) is the most widely used, both commercially and for its therapeutic properties. Aloe vera plants contain two major juice materials: first, a yellow exudate containing a high concentration of anthraquinone compounds that has been used throughout the centuries as a cathartic and for medicinal purges; and second, a clear mucilaginous gel that has been used since ancient times to treat burns and other wounds where it is thought to increase the rate of healing and reduce the risk of infection. See Grindlay, D.; Reynolds, T., J. Ethnopharmcol. 1986, 16(2–3), 117–151; and Joshi, S. P., J. Med. Aromat. Plant Sci. 1998, 20(3), 768–773.
Several chemical components of the Aloe gel are thought to be responsible for its wound healing and immunostimulatory properties. For example, the glycoprotein Aloctin A is reported to have antitumor and antiulcer effects (see Imanishi, K., Phyother. Res. 1993, 7, S20–S22), and a 29KD glycoprotein has been found to increase proliferation of normal human dermal cells (see Yagi, A.; Egusa, T.; Arase, M.; Tanabe, M.; Tsuji, H., Planta Med. 1997, 63(1), 18–21). Clearly, however, the major composition of Aloe gel comprises a mucilage of polysaccharide substances. Most of these polysaccharides are glucomannans, mannans or pectins having a range of molecular weights. A major focus of research has been on the carbohydrate fraction isolated from Aloe gel known as, “acemannan” which comprises a polydispersed β-(1,4)-linked acetylated mannan interspersed with O-acetyl groups.
One mechanism by which Aloe components may enhance wound healing is by activation of macrophages. Monocytes/macrophages are found in practically every tissue of the body where they are critical in coordinating immune responses and numerous biological processes. (see Elgert, K. D.; Alleva, D. G.; Mullins, D. W., J. Leukoc. Biol. 1998, 64(3), 275–290). These cells function as phagocytes, i.e., debridement agents and they produce growth factors that influence the angiogenesis stage of wound repair, (see Wilson, K., Nurs. Crit. Care 1997, 2(6), 291–296). The production of cytokines by macrophages requires activation of these cells and prolonged wound healing times in aged mammals may be symptomatic of impaired macrophage function, (see Ashcroft, G. S.; Horan, M. A.; Ferguson, M. W., Lab. Invest. 1998, 78(1), 47–58). In cancer, macrophages mediate tumor cytotoxicity functions through the production of cytokines and other immune factors (see Gordon, S., Res. Immunol. 1998, 149(7–8), 685–688). In order for macrophages to play a major role in adaptive and innate immunity they must respond effectively to environmental agents by first becoming activated (see Adams, D. O.; Hamilton, T. A., In The Natural Immune System: The Macrophage; Lewis, C. E., McGee, J. O'D., Eds.; Oxford University Press Inc.: New York, 1992; pp 75–114). Macrophage activation is mediated by proinflammatory transcription factors such as nuclear factor kappa B (NF-kappa B). Such transcription factors then control and modulate the activation/repression of an array of genes that mediate a variety of immune responses.
In unstimulated macrophages, NF-kappa B exists as inactive heterodimers sequestered by inhibitory-kappa B (I-kappa B) proteins within the cytosol. Agents that cause I-kappa B proteins to dissociate and degrade allow for the translocation of NF-kappa B dimers to the nucleus where they can activate transcription of downstream genes (see May, M. J.; Ghosh, S., Immunol. Today 1998, 19(2), 80–88). Target genes regulated by NF-kappa B include proinflammatory cytokines, chemokines, inflammatory enzymes, adhesion molecules and receptors (see Baeuerle, P. A.; Henkel, T., Annu. Rev. Immunol. 1994, 12, 141–179).
Pharmacological activities of acemannan include antiviral effects, (see Sheets, M. A.; Unger, B. A.; Giggleman, G. F. Jr.; Tizard, I. R., Mol. Biother. 1991, 3(1), 41–45), activation of macrophages (see Zhang, L.; Tizard, I. R., Immunopharmacology 1996, 35(2), 119–28), stimulation of T cells (see Womble, D.; Helderman, J. H., Immunopharmacol. Immunotoxicol. 1992, 14(1–2), 63–77) and induction of nitric oxide production (see Ramamoorthy, L.; Kemp, M. C.; Tizard, I. R., Mol. Pharmacol. 1996, 50(4), 878–884). Thus, acemannan exerts some of its therapeutic properties through macrophage activity. However, very high concentrations of acemannan, e.g., 200 to 2000 μg/mL (see Karaca, K.; Sharma, J. M.; Nordgren, R., Int. J. Immunopharmac. 1995, 17(3), 183–188) are typically required to achieve modest activation of macrophages. This indicates that acemannan is not very potent.